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Show ORIGINAL CONTRIBUTION Perceived Color of Hallucinations in the Charles Bonnet Syndrome Is Related to Residual Color Contrast Sensitivity Stephen A. Madill, FRCOphth, Gerassimos Lascaratos, MD, Geoffrey B. Arden, MBBS, PhD, and Dominic H. ffytche, MRCPsych Background: We sought to determine whether the change in cortical excitability secondary to deafferen-tation in patients with Charles Bonnet Syndrome ( CBS) who hallucinate in a predominant color or combination of colors is related to an alteration in color contrast thresholds and whether the change is specific to the color of the hallucination. Methods: We prospectively categorized each pa-tient's hallucinations using the Institute of Psychiatry Visual Hallucinations Interview. We measured color contrast thresholds with a computerized test designed to assess red- green and blue- yellow color confusion axes against a background of luminance noise. We calculated the ratio of red- green threshold to blue-yellow threshold ( R- G/ B- Y ratio) for each patient. Because central vision was impaired in all patients, we used a sectoral annular stimulus that projected to the retina at 12.5 eccentricity. Results: There were 10 patients with age- related macular degeneration and CBS who were halluci-nating in a predominant color or combination of colors at the time of recruitment. Patients halluci-nating in red, green, or a combination of red and green had R- G/ B- Y ratios of less than 1.0 ( n = 5). Patients hallucinating in blue, yellow, or a combina-tion of blue and yellow had R- G/ B- Y ratios of greater than 1.0 ( n = 2). Patients hallucinating in purple had ratios between the red- green and blue- yellow hallucinators ( n = 2). The 1 patient hallucinating in white had the lowest thresholds for red- green and blue- yellow confusion axes. Comparing the R- G/ B- Y ratios for the ‘‘ red/ green hallucinators'' and ‘‘ blue/ yellow hallucinators'' returned a significant result with Fisher's exact test ( P = 0.047, n = 7). Conclusions: Deafferentation and secondary cortical hyperexcitability in CBS have a correlate in psycho-physical threshold. This change in sensitivity relates specifically to the hallucinated color axis rather than across all colors. This is the first published evidence for cerebral hyperexcitability leading to a decrease in color contrast thresholds. ( J Neuro- Ophthalmol 2009; 29: 192- 196) A lthough the definition of Charles Bonnet syndrome ( CBS) varies ( 1,2), ophthalmologists and neurologists use the term when referring to certain types of visual hallucinations in the context of visual pathway pathologic lesions ( 3,4). The underlying mechanism is thought to be visual deprivation leading to cortical excitability ( release [ 5] or deafferentation phenomenon [ 6]), in effect a visual variant of the phantom limb phenomenon. Several lines of evidence support this mechanism. For example, increased cortical excitability follows ophthalmic lesions in a range of animal models ( 6) and in normal subjects with ‘‘ functional'' deafferentation after blindfolding ( 7). Furthermore, cortical hyperexcitability is found in patients with CBS and underlies individual hallucination episodes, with the location of spontaneous cortical activity defining the content of a hallucination ( 8). Thus, spontaneous activity in a region of cortex specialized for processing color information results in hallucinations of color, whereas activity in cortical regions receiving input about the face results in hallucinations of faces. In their investigation of the phenomenology of hallucinations associated with CBS, ffytche and Howard ( 9) identified previously undescribed types of hallucina-tions along with the known types of CBS hallucinations such as formed percepts of distorted faces and multiple images. One of these previously undescribed hallucinations Princess Alexandra Eye Pavilion ( SAM, GL), Edinburgh, UK; Henry Wellcome Laboratories ( GBA), Department of Visual Science, City University, London, UK; and Institute of Psychiatry ( DHf), London, UK. This article was presented as a poster at the ARVO 2005 Annual Meeting. G. B. Arden is a consultant for ChromaTest. Address correspondence to Stephen A. Madill, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh, EH3 9HA, UK; E- mail: samadill@ hotmail. com 192 J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 was that of ‘‘ hyperchromatopsia,'' or the perception of unnaturally vivid colors as amorphous blobs or regular patterns (‘‘ tessellopsia'') ( 9). In another study, 16% of patients reported hallucinations of hyperintense color ( 10). Patients often stated that the colors were more vivid than those of normal perception ( 9). Therefore, the hallucina-tions were not simply color memories. Using functional MRI scanning, ffytche et al ( 8) had previously demon-strated that hallucinations of colored blobs were associated with spontaneous phasic increases in activity in part of the fusiform gyrus, an area corresponding to V4, the pre-sumptive color center. We decided to investigate whether there is a change in cortical excitability among patients with CBS who hallucinate in a predominant color or combination of colors manifested as an alteration in color contrast sensitivity and, if so, whether the change is specific to the hallucinated color. Our hypothesis was that cortical hyperexcitability for a particular color confusion axis would manifest as increased color contrast sensitivity for that axis. METHODS We performed a prospective case series analysis including all patients who had CBS due to age- related macular degeneration ( AMD). Patients were recruited via an advertisement distributed to all the macular disease society local groups in the United Kingdom. We requested volunteers who were hallucinating in a predominant color or combination of colors at the time of recruitment. We categorized each patient's hallucinations by using the previously published Institute of Psychiatry Visual Hallucinations Interview ( 9,10). The structured questionnaire/ interview covers patient demographics, oph-thalmic and medical history ( including drug history), hallucinatory phenomenology, descriptive style, and ex-clusions discussed below ( see Appendix). The assessments were carried out by one investigator. The study was approved by the King's College Hospital research ethics committee and conformed to the principles of the Second Declaration of Helsinki. There are no standardized criteria to diagnose CBS ( 11), but we aimed to exclude patients with other common visual hallucination- related pathologic conditions. There could be no evidence of gross cognitive decline, psychosis, alcohol or drug abuse, or occipital/ temporal lobe epilepsy, as occipital and temporal auras may contain visual content ranging from simple unformed blobs to complex figures and objects ( 12). There could be no history of cerebrovas-cular disease, although we cannot completely exclude ischemia as the patients did not undergo scanning before recruitment. The hallucinations could not be limited to the margins of sleep as hallucinations before sleep ( hypnagogic hallucinations) or just after waking ( hypno-pompic hallucinations) may be normal phenomena ( 13). Color contrast sensitivitywas measured with a revised version of equipment used in previous work ( ChromaTest; CH Electronics, Bromley, UK) ( 14- 16). The computerized hue discrimination test was used to assess color contrast thresholds along red- green and blue- yellow color confusion axes with color contrast defined stimuli presented against a background of luminance noise. The luminance noise rendered the test relatively independent of environmental luminance or chromatic levels. The patient sat 1 m from the monitor and viewed the stimuli without a chin rest. The test has proved sensitive for monitoring subclinical changes in color contrast thresholds for patients with AMD ( 17) and diabetes ( 18) and, with a color contrast stimulus projecting 12.5 eccentric to fixation, sensitive in screening for glaucoma ( 19,20). It has also proved robust to yellowing of the aging lens ( 17). Because central vision was impaired in all patients, we used the sectoral color- contrasting annular stimulus subtending 45 of arc with a width of 2.5 and projecting to 12.5 eccentricity. The stimulus could be presented randomly in 1 of 4 locations ( superior and inferior nasal and superior and inferior temporal quadrants) ( Fig. 1). The annular stimulus was presented for 8 seconds. The stimulus lasted 0.1 second and was repeated every second. Thus the stimulus appeared to flash on and off 8 times during a single trial. The patients had to identify the quadrant in a 4- way forced choice protocol using a modified binary search technique ( 15). Depending on whether the identification was correct or incorrect, the color contrast of the stimulus was then increased or reduced. The computer program FIG. 1. Screen shot of stimulus in upper right quadrant. For R- G axis testing, the stimulus was red, presented against a green background; for B- Y axis testing, the stimulus was blue, presented against a yellow background. The stimulus was presented for 8 seconds at 1 Hz with saturation modulating sinusoidally along the specific color confusion line. 193 Charles Bonnet Syndrome J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 continued the test until the standard deviation of the mean calculated threshold was 1% of the maximum possible color modulation. Because patients with macular degeneration use the peripheral retina for viewing, they were able to maintain fixation to within an acceptable degree. We ran the test for red- green and blue- yellow axes of confusion, with test order counterbalanced across patients. The test took less than 10 minutes per axis. We gave the patients standardized instructions, then tested monocularly using only the eye with better visual acuity. We expressed the results as a percentage of the maximum possible modulation along the chosen color confusion line. Although we calculated the threshold in each quadrant, we used the average color contrast threshold for each axis of each patient to compare results. Control subjects with no evidence of AMD on ophthalmoscopy had one eye tested with the same protocol. Using a random number table, we determined which axis and which eye to test first. RESULTS We recruited 10 patients with CBS due to AMD. Their most recent hallucinatory episode had occurred within 1 month of testing. Their mean age was 75 years ( range 67- 92 years); there were 9 women and 1 man. Their median best- corrected Snellen visual acuity was 20/ 200. None of the patients was aware of any subjective alteration in color perception. The descriptions of each patient's hallucination and the thresholds for red- green and blue- yellow confusion axes are shown in Table 1. We calculated the ratio of red-green color contrast threshold to blue- yellow color contrast threshold ( R- G/ B- Y ratio) for each patient, also shown in Table 1. Patients hallucinating in red, green, or a combination of red and green (‘‘ red- green hallucinators'') had R- G/ B- Y ratios of less than 1.0 ( n = 5). Patients hallucinating in blue, yellow, or a combination of blue and yellow (‘‘ blue- yellow hallucinators'') had R- G/ B- Y ratios of greater than 1.0 ( n = 2). A comparison of the R- G/ B- Y ratios to the color axis hallucinated for red- green and blue- yellow hallucinators returned a significant result with Fisher's exact test ( P = 0.047, n = 7). Unexpectedly, patients hallucinating in purple had ratios between those of red- green and blue-yellow hallucinators ( n = 2). In addition, the 1 patient hallucinating in white had the lowest thresholds for red-green and blue- yellow confusion axes. We recruited 6 control subjects ( 5 women and 1 man, mean age 68 years, range 57- 75 years). The means of the controls' thresholds for each axis with standard errors are also shown in Table 1. DISCUSSION Our results suggest that deafferentation and second-ary cortical hyperexcitability in CBS have correlates in psychophysical thresholds and that patients hallucinating along a single color axis demonstrate better color contrast TABLE 1. Descriptions of each patient's hallucination with the thresholds for red- green and blue- yellow confusion axes and red- green/ blue- yellow ratio Patient Age ( years) Description of Hallucination Red- Green Contrast Threshold (%) Blue- Yellow Contrast Threshold (%) R- G/ B- Y Ratio 1 88 Blue lattice 5.4* 2.8 1.9 2 79 Blue circles and flower heads 4.5* 2.8 1.6 3 84 Purple crescents 7.5* 5.6 1.3 4 92 Single purple ring 6.3 7.4* 0.9 5 82 Red bricks 20.8 28.8* 0.7 6 86 Green and red squares 3.6* 6.8 0.5 7 75 Pink and green spots 4.6 10.1* 0.5 8 90 Orange bricks 11.5 39* 0.3 9 87 Red blobs 2.3* 12.5 0.2 10 67 White Catherine wheels 1.9* 2.2 0.9 Mean thresholds for controls ( SE) 2.1 ( 0.2) 2.0 ( 0.3) 1.0 R- G/ B- Y ratio, red- green/ blue- yellow ratio. * Color confusion axis tested first. 194 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Madill et al sensitivity for the particular axis hallucinated. This differ-ence in sensitivity seems to relate to the hallucinated color axis of confusion rather than across all colors. As far as we are aware, there has been no previously published evidence for cerebral hyperexcitability leading to a decrease in color contrast thresholds. Acquired alteration in color perception ( acquired dyschromatopsia) is a well- recognized feature of anterior visual pathway disease. It is broadly categorized by Ko ¨ llner's rule ( 21), which states that there is reduced red-green sensitivity for optic nerve disease and reduced blue-yellow sensitivity for retinal disease. That rule is useful although it has exceptions. Less commonly, acquired dyschromatopsia results from bilateral lesions of the inferior occipital cortex, which include the fusiform gyri and presumptively V4 ( 22). Cerebral problems with color perception can manifest as problems with hue discrimina-tion ( 23), with defects found in several different tests of color vision including the pseudo- isochromatic Ishihara plates and the Farnsworth- Munsell 100 hue test. ( 24,25). These cerebral conditions must be differentiated from visual agnosias, in which color perception is normal but the patient is unable to name or recognize colors. Cerebral achroma-topsics often report that colors have lost their brightness and appear gray ( 23), a different perception from that of our patients, who were not aware of any dyschromatopsia. Although there are no previous reports of cerebral hyperexcitability affecting color contrast thresholds, there are reports of the effects of deafferentation of the visual system manifesting as other phenomena. One example is sound- induced photism ( 26), in which sudden noises stimulate visual phenomena such as ameboid shapes and flashes of light in a group of patients with pathologic conditions causing partial physiologic deafferentation of the visual pathway. In that phenomenon, deafferentation of the lateral geniculate nucleus ( LGN) may lead to postsynaptic elements developing new receptive fields. Because the LGN can respond to sound as well as light, the new receptive fields of the deafferented visual system show heightened sensitivity to the sound impulses passing through the LGN. Our inferences are limited by our sample size, chiefly constrained by having to recruit patients with CBS who were hallucinating at the time of our study and whose hallucinations were limited to a predominant color or small category of colors. Small samples are vulnerable to bias. Despite randomization, both blue- yellow hallucinators had the blue- yellow axis tested second. It is therefore also worth noting that 7 of the 10 patients demonstrated lower color contrast thresholds for the second tested axis, suggesting that the results may be an artifact of the methodology. In defense of our conclusions, all red- green hallucinators had R- G/ B- Y ratios of less than 1, independent of which axis was tested first. In addition, a bias toward the second tested axis would not explain why the R- G/ B- Y ratios of purple hallucinators are found between the ratios for blue- yellow and red- green hallucinators. Finally, 5 of 6 control subjects performed better on the first tested axis, suggesting that there is not a significant learning effect inherent to the test. The area of retina affected by AMD is greater than the area of morphologic change evident on ophthalmos-copy ( 27). It is therefore fair to suggest that our stimuli, although projecting to 12.5 eccentricity, will be within the retina affected by AMD- related changes and thus within the zone of deafferentation. This fact would explain why almost all thresholds for the subjects with AMD are worse than those for the control subjects. Our results could be criticized for the over-representation of patients with red- green type hallucina-tions. AMD leads to a greater loss of blue- yellow than of red- green sensitivity ( 17). Therefore, the R- G/ B- Y ratios of the red- green hallucinators could be explained as being expected of any patient with AMD and thus unrelated to the color of their hallucinations. This criticism would actually support the validity of our results, as the blue- yellow and purple hallucinators ( with greater R- G impairment for the blue- yellow hallucinators and equal impairment of both axes for the purple hallucinators) are therefore unusual for patients with AMD and require an additional hypothesis for explanation. How deafferentation results in hallucinations of specific colors is unclear. Our results suggest that the predominant color hallucinated is linked to the color axis with better con-trast sensitivity. One explanation for this finding is that a relative loss of cortical inputs from one axis results in hyper-sensitivity, hallucinations, and a paradoxical improvement of contrast sensitivity in that axis. Alternatively, a selective loss of inputs from one axis may result in hallucinations related to the other, relatively preserved, axis. Further studies are required to distinguish these two possibilities. 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Do you see them with your eyes closed? 11. Do the visions go away if you move you eyes or blink? 12. Do the visions move when you move your eyes or move your head? 13. Are they in color and if so is the color normal, vivid or dull? 14. Are the visions like whole scenes, or individual objects/ figures? 15. Do visions usually change from one thing to another? 16. Flashes, lines, colors, zig- zags, Catherine wheels? 17. A complete figure/ group of figures? ( Were they small, in costume or uniform, wearing a hat, moving realistically?) 18. A facewithout a body? ( Was it realistic or caricature, ugly, prominent eyes or teeth, moving as if talking?) 19. Words, letters, musical notes, or numbers? 20. Vehicles? 21. Animals ( moving realistically?) 22. Regular patterns ( brickwork, netting, honey-combs, latticework, etc)? 23. Irregular patterns ( maps, hedges, bushes, etc)? 24. Furniture? 25. Houses and buildings? 26. Field of view covered with small particles ( rain drops, snowflakes, hundreds, and thousands, etc)? 27. Multiple copies of an image at the same time ( did they form a row?) 28. Surfaces filled with objects, patterns, or shapes? 29. Looked at something and found its image persisted even after you looked away? 30. Looked at something and found that its image returned some time later? 31. Visions brought on by motion ( being driven, on a train, etc.)? Exclusion questions 32. Visions associated with sound or talking? 33. Visions associated with dizziness, strange smells or unusual sensations? 34. Occurrence only in bed or when waking from sleep? 35. History of stroke, major psychiatric illness, epilepsy? 36. Frightening visions of small animals, spiders, snakes, maggots, etc.? Descriptive fluency 37. Describe a Christmas tree. 196 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Madill et al |
